Graft-versus-host disease (GVHD) is a most frequent complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is associated with significant morbidity and mortality. Mortality rates as a direct or indirect consequence of GVHD can reach 50% despite the prophylactic use of immunsuppressive drugs like cyclosporine, tacrolimus, ATG, methotrexate, and mycophenolate mofetil which are administered for prevention of GVHD. Two distinct types of GVHD are clinically recognized, acute and chronic. The acute form of the disease usually develops within the first three months after transplantation. The skin, liver and gastrointestinal tracts are the main targets of acute GVHD. Newly transplanted, donor lymphocytes react to the host tissue antigens, resulting in cell damage to a variety of organs. The incidence rate of acute GVHD is estimated at 30-50% among patients receiving transplant from HLA-identical sibling donors, and 50-70% in. patients receiving MA-matched unrelated transplants. Severe acute GVHD (grade III-IV) occurs in up to 20% of recipients of related donors (Champlin, Blood 2000; 95:3702-3709) and up to 35% of unrelated donors (Castro-Malaspina, Blood 2002; 99:1943-1951, McGlave, Blood 2000; 95:2219-2225, Jagasia, Blood 2012; 119:296-307). Non-relapse mortality in patients who develop acute GVHD has been estimated to be in the range of 28% to 92%. Long term survival after grade I acute GVHD is greater than 90%, contrasting with 80%, 30%, and 10% for grades II, III, and IV, respectively.
Chronic GVHD occurs in up to 60% of patients receiving HLA-identical sibling marrow grafts and 70% of patients receiving alternative donor marrow grafts who survive beyond day 100. (Lee, BBMT 2003; 9: 215-233). Symptoms of chronic GVHD usually present between 3 months and 2 years after allogeneic transplantation, about two thirds develop within the first 12 months. Manifestations of chronic GVHD may be restricted to single organ or tissue, but typically 2 or 3 organs are involved. The organs most commonly affected are the skin, mouth, and eyes, with more than 50% of patients demonstrating these manifestations. Other disease sites include the liver, lungs, gastrointestinal tract, musculoskeletal system, and female genital organs.
Chronic GVHD can lead to debilitating consequences such as joint contractures, loss of sight, end-stage lung disease, and mortality from infection. The 3 year risk of non-relapse mortality in patients with chronic
GVHD ranges from 28% to 48% depending on the extent of GVHD. Mortality rates are increased in patients with extensive disease (more than limited skin or liver involvement), progressive onset (chronic GVHD evolving directly from acute GVHD), thrombocytopenia, and HLA-non-identical donors. The overall survival rate is 42%, but patients with progressive onset of chronic GVHD have a survival rate of 10%.
Altogether, only less than 20% of transplanted patients do not develop either acute or chronic GVHD (Flowers, Blood 2011; 117(11); 3214-3219).
It is well accepted that acute and chronic GVHD are unique different processes. This fact is emphasized by the observations that chronic GVHD can occur without prior acute GVHD, and that interventions that are successful in preventing or treating acute GVHD most commonly fail to decrease chronic GVHD (Pavletic, Blood 2005; 106:3308-3313, Thomas hematopietic cell transplantation, 4th edition, page 1307, Wiley-Blackwell). Most investigators now consider chronic GVHD as a disease of immune dysregulation that involves donor-derived immune cells and host cell populations and tissues. This process is likely initiated by donor-derived T cells and is both alloreactive (directed against the recipient's histocompatibility antigens) and autoreactive (directed against antigens present on both the donor and recipient). The activated immune response then proceeds unchecked by the thymic or peripheral mechanisms of deletion and immunoregulation. Critical donor or recipient tolerance-promoting mechanisms may be absent.
Conventional treatment of chronic GVHD requires prolonged periods of systemic immunosuppressive therapy with potent drugs such as corticosteroids and cyclosporine. Agents such as mycophenolate mofetil, rapamycin (sirolimus), imatinib and rituximab are used in patients with steroid-refractory chronic GVHD. However, these treatments have limited effectiveness, and cause very often severe adverse effects. Only 50% of patients with chronic GVHD are able to discontinue immunosuppressive treatment within 5 years after diagnosis, and 10% require continued treatment beyond 5 years. The remaining 40% die or develop recurrent malignancy before chronic GVHD resolves. 5 year survival rates of patients with high risk chronic GVHD (platelet counts <100,000/microliter or progressive onset from aGVHD) is only 40-50%.
Thus, developing innovative strategies to prevent and treat GVHD is a major unmet need.
The cannabis plant (Cannabis saliva) has been in use for medical purposes for thousands of years. Medical Cannabis is nowadays prescribed for prevention of nausea and vomiting associated with cancer chemotherapy, and for the treatment of anorexia associated with AIDS and cancer.
Cannabis plants produce a group of natural chemicals called Cannabinoids, among them Δ9-tetrahydrocannabinol (THC), Cannabidiol and ajulemic acid. Cannabidiol (CBD) was first isolated by Adams [J. Amer. Chem. Soc., 6: 2194 (1940)] and its structure was elucidated by Mechoulam and Shvo in 1963 (Tetrahedron 19: 2073). The synthesis of cannabidiol in its racemic form and its natural form were reported in J. Amer. Chem. Soc. 87:3273-3275 (1965), and in Helv. China. Acta. 50:719-723 (1967). Cannabidiol is the most abundant cannabinoid, contributing up to 40% of Cannabis extracts, having no psychotropic effects, as opposed to THC.
The immune-modulatory and anti-inflammatory properties of Cannabidiol have been shown in animal models of various inflammatory diseases including multiple sclerosis (Kozela, BJP, 2011), diabetes mellitus (Weiss, Autoimmunity 2006), inflammatory bowel disease (Borrelli, J Mol Med 2009) and rheumatoid arthritis (Malfait, PNAS 2000), CBD mediates its anti-inflammatory effects by suppressing T cell proliferation, by shifting the balance from TH1 to Th2 cytokines, inhibiting the pro-inflammatory cytokine release including INFγ, TNFα, IL-1β, IL-6, IL-17 and stimulating the anti-inflammatory cytokine release including IL-4, IL-5, IL-10, IL-13 (Mechoulam, Chem Biodivers 2007, Carrier PNAS 2006, McHugh, Mol Pharmacol 2007, Lee, Int Immunopharmacol 2008, Weis, Autoimmunity 2006, Borrelli, J Mol Med 2009, Kozela, J Neuroimmune Pharmacol 2013, Kozela BJP 2011, Malfait, PNAS 2000).
Unlike Δ9-tetrahydrocannabinol (THC), cannabidiol binds very weakly to CB1 and CB2 receptors [Mechoulam, R. & Hanus, L. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem Phys Lipids 121:35-43 (2002)].
CBD does not induce psychoactive or cognitive effects and is well tolerated by humans without significant adverse effects [Varga, K., Lake, K., Martin, B. R. & Kunos, G.
CBD has also been shown to be superior to THC, in inhibiting pro-inflammatory IL-I, TNFα and IFNγ release by peripheral blood mononuclear cells. [Watzl, B., Scuderi, P. and Watson, R. R. Influence of marijuana components (THC and CBD) on human mononuclear cell cytokine secretion in vitro. Adv Exp Med Biol 288:63-70 (1991);]
U.S. Pat. No. 6,410,588 describes the use of cannabidiol for treating inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's Disease, and medicinal preparations containing CBD for use in treating such diseases.
PCT/IL01/00537 describes pharmaceutical compositions comprising cannabidiol derivatives which have analgesic, antianxiety, anticonvulsive, neuroprotective, antipsychotic and anticancer activity.
Although the prior art teaches several potential therapeutic effects and uses of CBD it does not describe or suggest use of CBD or derivatives thereof in treating GVHD.
Therefore, it is an object of the invention to provide Cannabidiol compositions for use in the prevention and treatment of GVHD.
A further object of the invention is the provision of a method of treating and preventing the onset of GVHD by administering a Cannabidiol composition to a patient undergoing transplantation.
A still further object of the invention is the provision of the use of Cannabidiol compositions in the preparation of medicaments for the prevention or treatment of GVHD.
Further purposes and advantages of this invention will appear as the description proceeds.